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<p>Abstract</p> <p>Background</p> <p>Nontypeable <it>Haemophilus influenzae</it> (NTHi) is a significant human pathogen responsible for respiratory tract infections and the most common cause of recurrent otitis media. Type II toxin-antitoxin (TA) systems are genetic elements that code for a stable protein toxin and a labile antitoxin that are thought to be involved in metabolic regulation of bacteria by enabling a switch to a dormant state under stress conditions. The contribution to infection persistence of the NTHi TA loci <it>vapBC-1</it> and <it>vapXD</it> was examined in this study.</p> <p>Results</p> <p>Deletions in <it>vapBC-1, vapXD</it> and <it>vapBC-1 vapXD</it> significantly decreased the survival of NTHi co-cultured with primary human respiratory tissue at the air-liquid interface and in the chinchilla model of otitis media. The TA deletions did not affect the growth dynamics of the mutants in rich media, their ultra-structural morphology, or display appreciable synergy during NTHi infections. The toxin and antitoxin proteins of both pairs heterodimerized <it>in vivo</it>. Consistent with our previous findings regarding the VapC-1 toxin, the NTHi VapD toxin also displayed ribonuclease activity.</p> <p>Conclusions</p> <p>We conclude that the <it>vapBC-1</it> and <it>vapXD</it> TA loci enhance NTHi survival and virulence during infection <it>in vitro</it> and <it>in vivo</it> using a mechanism of mRNA cleavage, and that these conserved TA pairs represent new targets for the prophylaxis and therapy of otitis media and other NTHi-caused mucosal diseases.</p>